Successful Topical 5-Aminolevulinic Acid Photodynamic Therapy in the Treatment of Resistant, Multiple Palmar Warts: Two Clinical Cases with General Evidence Analysis

Introduction

Viral warts, clinically known as verrucae, represent a common dermatological condition instigated by the human papillomavirus (HPV). This DNA virus, belonging to the Papillomaviridae family, comprises over 350 identified types. Although some HPV types are linked to specific clinical presentations, including cutaneous or mucosal lesions, many exhibit overlapping features or have yet to be fully characterized in clinical contexts [1, 2]. HPV selectively infects keratinocytes, inducing hyperproliferation that culminates in the formation of benign lesions on the skin or mucosa with a prevalence in the general population ranging from 7% to 12% [3]. The treatment of these warts poses challenges due to their endophytic growth and the presence of a thick keratinized layer [4]. Periungual warts, commonly linked to HPV genotypes 1, 2, 4, 27 and 57 are particularly troublesome, given their proximity to the nail matrix and the associated risk of pain, discomfort and nail dystrophy [5]. Standard therapeutic approaches for periungual warts including cryotherapy, salicylic acid, laser therapy are often associated with high recurrence rates, significant discomfort and potential scarring [6]. These limitations highlight the need for alternative therapies that maximize effectiveness while prioritizing patient comfort and minimizing adverse effects. Photodynamic therapy (PDT) involves the application of a photosensitizing agent such as 5-aminolevulinic acid (5-ALA), which preferentially accumulates in infected cells [7]. Upon activation by a specific light source, the photosensitizer generates reactive oxygen species that induce cytotoxic effects, effectively targeting pathological cells.

Objective

The aim of the study was to present 2 cases of patients who underwent PDT for treatment-resistant periungual warts and to explore methods that may enhance the effectiveness and efficacy of PDT.

Case reports

Case 1

The patient is a 28-year-old man with multiple verrucae on 8 fingers in the periungual area after unsuccessful, multiple treatments by curettage, cryotherapy with liquid nitrogen, topical salicylic acid and 5-fluorouracil, imiquimod with no clinical improvement observed. The patient has been qualified for 5-ALA PDT. Figure 1 A presents the initial state before the first PDT session. A 10% topical 5-ALA gel was applied under occlusion to the warts, extending to a 1-cm margin of surrounding healthy skin and incubated for 3 hours. Subsequently, the treatment area was exposed to red light at 635 nm with a total dose of 37 J/cm². Photodynamic therapy sessions were performed at monthly intervals – 3 PDT treatments were needed to achieve full remission. Figure 1 B presents the state a month after the first PDT session, figure 1 C after the second and figure 1 D after the third session. In dermoscopy, no features of warts were identified. No recurrence of warts was noted during the 6-month follow-up even though the patient continues to bite the cuticles despite repeated requests to stop. The patient found PTD to be less painful than cryotherapy. He rated the pain level as 3 out of 10 on the Numerical Rating Scale (NRS) and he only experienced a mild burning effect. No other side effects have been reported.

Case 2

The second patient is a 51-year-old woman with multiple viral warts on both hands present as cauliflower-like papules with a rough surface ranging in size from a half to 1 cm. Figure 2 A presents the initial state of viral wart on the right thumb. A 10% 5-ALA topical gel was administered to the warts under occlusion, covering an additional 1-cm margin of adjacent healthy skin, followed by a 3-hour incubation. The treatment site was then irradiated with red light at a wavelength of 635 nm, delivering a total energy dose of 37 J/cm². Figure 2 B presents the state after the second PDT. While most of warts on other fingers were treated after 2 sessions of PDT, figures 2 C, D present the right thumb on which a frogspawn pattern and dotted vessels are visible. Before the third PDT the patient was advised to administer 5-fluorouracil cream twice daily for a week. 5-FU pretreatment increases the PpIX (protoporphyrin IX) concentration and is able to enhance the cell death upon illumination. Figures 3 A, B present the state after the third PDT session and figures 3 C, D after the fourth one. Both with 5-FU pretreatment. In addition to the cut visible on the picture and caused by a sharp instrument, two separate areas with outbreaks of viral warts can also be observed. Before the 5th ALA PDT (figs. 3 E, F), physical pretreatment with CO₂ fractional ablative laser has been applied to cause deeper penetration of the photosensitizer. After 5-ALA PDT sessions the patient experienced full clinical remission without any side effects.

Discussion

Management of cutaneous warts typically follows a progressive approach, beginning with first-line treatments like salicylic acid and cryotherapy [6]. When these methods prove inadequate, options such as curettage, 5-fluorouracil and imiquimod provide alternative strategies for effective wart removal. Treating periungual warts presents unique challenges due to the risk of the nail matrix damage from invasive procedures. According to Kore and Anjankar, combination therapies – particularly cryotherapy paired with salicylic acid – have shown higher clearance rates compared to a single-agent treatments [8]. Common adverse effects of cryotherapy include pain, blistering and changes in pigmentation with hypo- or hyperpigmentation being more frequent in individuals with darker skin tones [9]. More intensive treatments also carry risks of tendon or nerve injury and onychodystrophy, particularly in the context of periungual warts [10]. The discomfort associated with cryotherapy often leads to higher dropout rates, while recurrence of the warts can reduce patient confidence in the treatment, resulting in less satisfactory outcomes.
The reported cases illustrate the challenge that can be encountered in daily clinical practice including presence of resistant-to-treatment, multiple warts in a difficult, periungual area. Therefore, alternative treatments are urgently needed. The difficulty is the absence of a specific scale dedicated to assessing plantar warts. However a dermatoscopic image has been utilized in clinical and scientific research [11]. Recent advancements in therapeutic approaches have introduced photodynamic therapy which has shown high efficacy and notably lower recurrence rates. PDT is a non-invasive treatment that precisely targets the affected tissue and is widely applied for actinic keratoses and superficial nonmelanoma skin cancers. Its mechanism relies on the photosensitizer 5-aminolevulinic acid which induces oxidative damage in abnormal cells upon exposure to visible light [12]. Due to its low molecular weight, 5-ALA efficiently penetrates the stratum corneum. For optimal absorption, a 10% ALA gel formulation is applied to the wart-affected areas and a surrounding 1-cm margin of healthy skin with occlusion for a 3-hour incubation period.
5-ALA is an endogenous precursor in the heme biosynthesis pathway, converting into the active photosensitizer protoporphyrin IX (PpIX) within cells [13]. Although enzymes involved in heme synthesis are broadly expressed across human cells, the higher enzymatic activity in transformed cells results in a selective buildup of PpIX within their mitochondria. After the 3-hour incubation, excess ALA is removed and the target skin area is exposed to visible light ranging from 400 to 700 nm [14]. The choice of light source in PDT is crucial, affecting photosensitizer excitation, tissue penetration depth and treatment efficacy as well as side effects. PpIX absorption peaks at 405 nm while the absorption at 635 nm allows for deeper tissue penetration [15]. Accordingly, light sources emitting at 635 nm are used for conditions that require enhanced penetration, such as condyloma acuminatum and treatment-resistant warts.
Following irradiation with a specific wavelength, the excessive accumulation of protoporphyrin IX in mitochondria generates reactive oxygen species (ROS), primarily singlet oxygen, which induces cell death. ROS can chemically modify various intracellular components, including proteins and DNA, leading to either necrosis or apoptosis if the damage is substantial. Necrosis – a non-programmed form of cell death, occurs when the cytoplasm becomes vacuolated and the cell membrane disintegrates, triggered by the release of numerous pro-inflammatory mediators due to oxidative stress. Conversely, apoptosis is a genetically encoded, energy-dependent process characterized by a sequential series of events, including the cleavage of chromosomal DNA into nucleosomal fragments and membrane blebbing, ultimately resulting in cell death [16]. Additionally, research by Giomi et al. demonstrated that PDT induces a localized immune response, releasing inflammatory mediators (IL-2, IL-1β and TNF-α) and enhancing immunity [17]. Furthermore, fibroblasts secrete matrix metalloproteinase-1 during PDT, contributing to immunomodulatory effects. Thus, PDT is advantageous for patients with compromised immunity [6].
For effective eradication of palmoplantar warts without recurrence, photodynamic therapy should be administered across multiple sessions at regular intervals. PDT efficacy can be further enhanced by strategies that improve both the concentration and penetration of ALA. In our approach, we incorporated a pretreatment with topical 5-fluorouracil (5-FU) – a uracil analogue that impedes DNA and RNA synthesis. By inhibiting cellular division and inducing cell cycle arrest, 5-FU limits viral proliferation and spread [18]. When delivered via intralesional injection, 5-FU achieves high local concentrations, however this method often causes significant pain and ulceration, limiting its widespread use [8]. Therefore, we opted for a topical application of 5-FU twice daily for 1 week prior to PDT. This pretreatment markedly elevates PpIX levels in abnormal cells, leading to enhanced cell death upon light activation. This effect likely results from modulation of heme pathway enzymes, including the upregulation of coproporphyrinogen oxidase and downregulation of ferrochelatase, thereby amplifying PDT’s cytotoxic impact [19]. An additional pretreatment strategy for complete wart eradication and prevention of recurrence involves the use of a fractional CO2 ablative laser. The limited penetration capacity of photosensitizers presents a key challenge in PDT, particularly with hyperkeratotic lesions where photosensitizer absorption depth is notably reduced. The CO₂ laser addresses this by creating microchannels up to 1500 µm deep within the skin, allowing for a more uniform distribution of porphyrins across the affected tissue [20]. These vertical channels, surrounded by a thin rim of coagulated tissue, form microscopic treatment zones without generating an epidermal necrotic layer. Haedersdal et al. investigated the enhancement of drug delivery for ALA and MAL through the use of a CO₂ ablative fractional laser (AFXL). Their findings demonstrated that AFXL significantly improved the topical absorption of porphyrin precursors when followed by a 3-hour application of MAL. This laser pretreatment created microchannels up to 3 mm deep within the skin, facilitating a homogenous distribution of porphyrins across the treated area [21]. Evidence from a meta-analysis by Piaserico et al. shows enhanced PpIX fluorescence in CO₂ laser-pretreated skin, underscoring the therapeutic benefit of combining ablative laser with ALA-PDT [22]. This combined approach exhibits a synergistic effect in managing periungual warts and allows for reduced incubation times of the photosensitizer, offering practical advantages in clinical application.
Acute adverse events during and after PDT include pain, erythema and crusting. In contrast, the primary adverse reactions to cryotherapy are pain, blisters, exudation and infection. Our patients reported that pain experienced during periungual cryotherapy was more severe than the pain during and after photodynamic therapy. PDT-induced pain occurs almost immediately after treatment. Although the mechanism of PDT pain is not yet fully understood, it is generally accepted that inflammation related to cell necrosis interacts with myelinated or unmyelinated nerve fibers [7]. PDT-induced pain is often described as a burning sensation that peaks within the first few minutes of treatment. Pain can be alleviated with local anesthetics, but only those with a neutral or acidic pH as ALA becomes unstable in an alkaline environment [23]. Unpleasant pain or previous experiences of prolonged pain can be mitigated with cyclooxygenase antagonists. PDT is noted for its excellent cosmetic results. It preserves the structure and functional activity of collagen and minimizes scarring. Our patients experienced better cosmetic outcomes with PDT compared to cryotherapy with fewer adverse effects such as hyperpigmentation or scarring. Sanclemente et al. in clinical studies have provided evidence that PDT may also reduce photodamage [24].

Conclusions

Clinical case reports from our institution, alongside evidence from the literature, confirm the effectiveness of photodynamic therapy in managing treatment-resistant periungual warts. PDT is generally well tolerated by patients and achieves excellent cosmetic outcomes. However, the limitations of PDT include the lengthy incubation time required for ALA and the need for multiple illumination sessions to secure complete resolution and minimize the recurrence risk. Additionally, the restricted availability and relatively high cost of PDT may limit its practicality. Consequently, PDT is not universally recommended for all viral warts but can serve as a valuable option for managing persistent warts in specific, difficult-to-treat locations.

Funding

No external funding.

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

References